When an animal encounters antigen, the immune system has the potential to respond in several ways. The animal can develop a strong effector response and long-lived memory that confers future immunity, or it can be induced to become unresponsive to the antigen at both the present time and in the future. The first response is necessary for protection against pathogens, the second essential for the prevention of autoimmunity. How is this crucial decision made? Our experiments will investigate a unique in vivo model of clonal deletion and anergy to investigate the conditions that lead to self-tolerance. We will determine what T cell subsets are susceptible to and involved in the induction of tolerance, what kinds of antigenic stimulation elicit tolerance rather than positive immune responses, and what lymphokines regulate these responses. To accomplish these goals we will study the induction of anergy in TCR transgenic mice in response to the bacterial superantigen, SEA. In this model, the great majority of T cells are CD4+ and become unresponsive, allowing us an unprecedented opportunity to characterize anergy and anergic cells. We will also investigate how distinct T cell subsets and lymphokines promote or suppress toxic shock in a related model. These experiments should provide important insights into immune regulation which can be applied as potential therapies to prevent unwanted reactivity on one hand, and to suggest approaches to potentiate protective immune responses, on the other. They may also provide clues for therapeutic intervention to prevent or ameliorate toxic shock syndromes induced by bacterial superantigens.